Non-neuronal acetylcholine as an endogenous regulator of proliferation and differentiation of Lgr5-positive stem cells in mice

Toshio Takahashi, Hiroe Ohnishi, Yuki Sugiura, Kurara Honda, Makoto Suematsu, Takashi Kawasaki, Tomonori Deguchi, Takeshi Fujii, Kaoru Orihashi, Yoshitaka Hippo, Takehiro Watanabe, Tohru Yamagaki, Shunsuke Yuba

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Abstract

Non-neuronal acetylcholine (ACh) is predicted to function as a local cell signaling molecule. However, the physiological significance of the synthesis of non-neuronal ACh in the intestine remains unclear. Here, experiments using crypt-villus organoids that lack nerve and immune cells in culture led us to suggest that endogenous ACh is synthesized in the intestinal epithelium to evoke growth and differentiation of the organoids through activation of muscarinic ACh receptors (mAChRs). The extracts of the cultured organoids showed a noticeable capacity for ACh synthesis that was sensitive to a potent inhibitor of choline acetyltransferase. Imaging MS revealed endogenous ACh localized in the epithelial layer in mouse small intestinal epithelium in vivo, suggesting that there are non-neuronal resources of ACh. Treatment of organoids with carbachol downregulated the growth of organoids and the expression of marker genes for epithelial cells. On the other hand, antagonists for mAChRs enhanced the growth and differentiation of organoids, indicating the involvement of mAChRs in regulating the proliferation and differentiation of Lgr5-positive stem cells. Collectively, our data provide evidence that endogenous ACh released from intestinal epithelium maintains homeostasis of intestinal epithelial cell growth and differentiation via mAChRs in mice.

Original languageEnglish
Pages (from-to)4672-4690
Number of pages19
JournalFEBS Journal
Volume281
Issue number20
DOIs
Publication statusPublished - 2014 Oct

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Keywords

  • Cholinergic system
  • Gut
  • Lgr5
  • Non-neuronal acetylcholine
  • Organoid

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Takahashi, T., Ohnishi, H., Sugiura, Y., Honda, K., Suematsu, M., Kawasaki, T., Deguchi, T., Fujii, T., Orihashi, K., Hippo, Y., Watanabe, T., Yamagaki, T., & Yuba, S. (2014). Non-neuronal acetylcholine as an endogenous regulator of proliferation and differentiation of Lgr5-positive stem cells in mice. FEBS Journal, 281(20), 4672-4690. https://doi.org/10.1111/febs.12974